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Investigational drug could have disease-modifying effect in sickle cell disease

Conference
American Chemical Society Spring 2021 Meeting
Reuters Health - 12/04/2021 - An investigational small molecule discovered by scientists at Fulcrum Therapeutics has the potential to address the root cause of sickle cell disease, early research suggests.

Current therapies for sickle cell disease are "suboptimal" and mainly address symptoms, Dr. Ivan Efremov, senior director and head of medicinal chemistry at Fulcrum Therapeutics, in Cambridge, Massachusetts, said in a presentation during the spring meeting of the American Chemical Society (ACS).

The Fulcrum drug, now known as FTX-6058, works by boosting levels of fetal hemoglobin, a healthy form of hemoglobin that adults don't normally make, and therefore is a "disease-modifying approach," he said.

Sickle cell disease (SCD) is an inherited disorder of red blood cells caused by a mutation in the HBB gene that causes hemoglobin to adopt a rigid sickle shape that interferes with the delivery of oxygen to tissues.

SCD patients are prone to anemia, pain, infection, stroke, heart disease, pulmonary hypertension, kidney failure and liver disease and have reduced life expectancy.

Patients with SCD don't start life with defective hemoglobin. Before birth, fetal hemoglobin carries oxygen normally. After birth, however, cells stop making fetal hemoglobin and switch to an adult version, which is defective in patients with SCD, Dr. Efremov explained.

Most adults still make some fetal hemoglobin but this typically accounts for less than 1% of their total hemoglobin. Some people, including a proportion of patients with SCD, have a condition called hereditary persistence of fetal hemoglobin.

"Interestingly," Dr. Efremov said, SCD patients with hereditary persistence of fetal hemoglobin have markedly decreased severity of symptoms. The more fetal hemoglobin they produce, the milder and the fewer symptoms they have. When the levels of fetal hemoglobin approach 30%, these patients are often asymptomatic, he noted.

Hereditary persistence of fetal hemoglobin provides "genetic validation" for the disease-modifying approach that FTX-6058 represents, he said.

FTX-6058 increases fetal hemoglobin levels by blocking the activity of a protein called embryonic ectoderm development (EED). In cell and murine models, FTX-6058 showed an increase in fetal hemoglobin levels up to roughly 30% of total hemoglobin.

Increasing fetal hemoglobin to this level has the potential to prevent or reduce disease-related pathophysiology and reduce the risk of recurring events such as vaso-occlusive crises and hemolysis, Dr. Efremov explained.

FTX-6058 has an "impressive pharmacological profile" that could make it a "transformative therapy" in SCD, he said.

Fulcrum is actively enrolling healthy volunteers in a phase-1 study evaluating the safety, tolerability and pharmacokinetics and optimal dosing of FTX-6058.

Early results "support once-a-day oral administration, which obviously offers significant convenience to patients," Dr. Efremov said.

In email to Reuters Health, Christi Waarich, director, investor relations and corporate communications at Fulcrum, said the company is “on track” to report data from the phase 1 trial “mid-year 2021 and initiate a clinical trial in sickle cell disease patients by year-end.”

"We are excited that we developed an approach that can follow this attractive clinical hypothesis that increasing fetal hemoglobin can treat sickle cell disease," Dr. Efremov said in his presentation.

Beyond SCD, Fulcrum is also considering a clinical strategy to explore the use of FTX-6058 in people living with beta-thalassemia, a blood disorder in which hemoglobin production is reduced.

SOURCE: https://bit.ly/3wNkalC American Chemical Society Spring 2021 Meeting, online April 5-30, 2021.

By Megan Brooks



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